Noise is the most common occupational and environmental hazard. Noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, after age-related hearing loss (presbycusis). Although promising approaches have been identified for reducing NIHL that are mainly based on the free radical pathway, currently there are no effective medications to prevent NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. In this proposal, we have turned this difficulty into an advantage by asking whether NIHL can be effectively prevented by a combination therapy targeting multiple signaling pathways. The immediate goal of this work is to explore this therapeutic direction for NIHL. The long-term goal is to develop an effective drug combination that dramatically prevents permanent noise-induced hearing loss. We have recently found that antiepileptic drugs blocking T-type calcium channels have both prophylactic and therapeutic effects for NIHL. NIHL can also be prevented by an up-regulation of glucocorticoid signaling pathways. In the R21 phase of this application, we will develop a combination therapy with anticonvulsants and synthetic glucocorticoids in one mouse NIHL condition, which has dramatic changes for both temporary and permanent threshold shifts. In the R33 phase, we will expand to two other NIHL mouse models that are similar to human conditions caused by a nearby explosion or manufacturing noise. We will also determine if the similar combination therapy can ameliorate permanent hearing loss in chinchillas. The innovative aspects of our approach are two-fold: (1) we will focus on FDA-approved drugs, which have already been extensively studied in animals with abundant pharmacological information; (2) the strategy of our combination therapy is to intervene in multiple signaling pathways instead of focusing only on the well-studied free radical pathway. This pharmacological approach may also reveal novel molecular targets critical to the development of NIHL. We are aware of the high-risk nature of this project because we do not know whether intervention in multiple signaling pathways will have a synergistic effect against NIHL. However, synergistic effects have been observed in drug combination treatments for acquired immunodeficiency syndrome and cancers. Our study can potentially have a high impact not only in the field of NIHL but also in other areas of communication science. For example, if successful, a similar approach can be explored for the treatment of presbycusis and tinnitus. In summary, this proposal will develop a paradigm-shifting approach to test novel drug combinations against NIHL.